rs587778738

Variant names:

• chr16-2084328-G-A
• rs587778738
• NM_000548.5:c.4106G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_000548.5(TSC2):​c.4106G>A​(p.Arg1369Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,460,376 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1369W) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4 O:1
• Conservation: PhyloP100: 2.83

Genes affected

TSC2 (HGNC:12363): (TSC complex subunit 2) This gene is a tumor suppressor gene that encodes the growth inhibitory protein tuberin. Tuberin interacts with hamartin to form the TSC protein complex which functions in the control of cell growth. This TSC protein complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18717614).
• BP6: Variant 16-2084328-G-A is Benign according to our data. Variant chr16-2084328-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135386.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, not_provided=1, Likely_benign=3, Benign=1}.
• BS2: High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.4106G>A	p.Arg1369Gln	missense_variant	Exon 34 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.4106G>A	p.Arg1369Gln	missense_variant	Exon 34 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000241 AC: 6 AN: 248622 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000895

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1460376 Hom.: 0 Cov.: 33 AF XY: 0.00000826 AC XY: 6 AN XY: 726478

Gnomad4 AFR exome AF: 0.0000299 AC: 1 AN: 33478

Gnomad4 AMR exome AF: 0.0000895 AC: 4 AN: 44708

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.0000504 AC: 2 AN: 39700

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86240

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 52012

Gnomad4 NFE exome AF: 0.00000360 AC: 4 AN: 1111966

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000986 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tuberous sclerosis 2 Uncertain:2 Benign:3

Nov 07, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 08, 2021

New York Genome Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 06, 2024

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Feb 16, 2022

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Nov 30, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1369Q variant (also known as c.4106G>A), located in coding exon 33 of the TSC2 gene, results from a G to A substitution at nucleotide position 4106. The arginine at codon 1369 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

TSC2-related disorder Uncertain:1

Apr 11, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TSC2 c.4106G>A variant is predicted to result in the amino acid substitution p.Arg1369Gln. This variant was reported in an individual with autism spectrum disorder (Table S3, Saskin et al. 2017. PubMed ID: 28250423; g.2074330 hg18 in Table 1, Schaaf et al. 2011. PubMed: 21624971). However, the variant was also reported in a healthy control (g.2134329 hg19 in Table S1, Bodian et al. 2014. PubMed ID: 24728327). This variant is reported in 0.011% of alleles in individuals of East Asian descent in gnomAD and has conflicting interpretations ranging from uncertain to benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/135386/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Uncertain	0.010
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.19	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	0.64	N;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.44	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Uncertain	0.46
Sift	Benign	0.19	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Sift4G	Benign	0.50	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Polyphen		0.72	P;.;.;.;B;B;.;.;B;B;.;.;.;.;.
Vest4		0.33
MVP		0.94
ClinPred		0.066	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.065
gMVP		0.24
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587778738; hg19: chr16-2134329; COSMIC: COSV105862579;